EP A1 (19) (11) EP A1 (12) EUROPEAN PATENT APPLICATION. (43) Date of publication: Bulletin 2007/27

Transcription

1 (19) (12) EUROPEAN PATENT APPLICATION (11) EP A1 (43) Date of publication: Bulletin 07/27 (21) Application number: (1) Int Cl.: A61K 9/14 (06.01) A61K 9/ (06.01) A61K 31/216 (06.01) (22) Date of filing: (84) Designated Contracting States: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR Designated Extension States: AL BA HR MK YU (71) Applicant: Teva Pharmaceutical Industries Ltd Petah Tiqva (IL) (72) Inventors: Lerner, Itzhak E. Petach Tikva 494 (IL) Rosenberger, Vered Modiin, (IL) Flashner-Barak, Moshe Petach Tikva (IL) Drabkin, Anna Tzur Hadassa. 9987,P.O.B 221 (IL) Moldavski, Naomi D.N HaNegev, 8492 (IL) (74) Representative: Gallagher, Kirk James et al D Young & Co 1 Holborn London EC1N 2DY (GB) (4) Pharmaceutical formulations of fenofibrate having improved bioavailability (7) Provided are pharmaceutical compositions of fenofibrate, and dosage forms containing them, that include fenofibrate, a polyethylene glycol, and a polethylene - polypropylene glycol; wherein the compositions are made by subliming a sublimable carrier from a combination of fenofibrate, the polyethylene glycol, and the polethylene - polypropylene glycol with the sublimable carrier, for example menthol. EP A1 Printed by Jouve, 701 PARIS (FR)

2 Description FIELD OF THE INVENTION [0001] The present invention relates to pharmaceutical compositions that include fenofibrate, a polyethylene glycol, and a polyethylene-polypropylene glycol, wherein the composition is made by sublimation of a sublimable carrier from a solid solution containing fenofibrate, a polyethylene glycol, a polyethylene-polypropylene glycol, and a sublimation carrier like menthol. BACKGROUND OF THE INVENTION [0002] Fenofibrate, (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester) is one of the fibrate class of drug. It is available as both capsules and tablets. Fenofibrate is apparently a prodrug. The active moiety is reportedly the metabolite fenofibric acid which is reported to be produced in the body by the action of esterases. When fenofibrate is administered, apparently no intact fenofibrate is found in the plasma (Physician s Desk Reference 8th ed. 04 pages 22 - (PDR)). [0003] Fenofibrate has very poor solubility in water. That is, it is a poorly water soluble drug. Despite its poor solubility in water, it is reported to be absorbed to a therapeutically acceptable degree when dosed in the "fed state" but less so when dosed in the "fasted state". The true "bioavailability" of the metabolite fenofibric acid is uncertain because much of it is understood to be metabolized to the glucuronide in both presystemic and first pass sites. [0004] The absolute bioavailability of fenofibrate cannot supposedly be determined because it is insoluble in media suitable for intravenous injection. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronide conjugate, and % was excreted in the feces. (PDR) The absorption of fenofibrate is understood to be increased when administered with food. The extent of absorption from orally administered tablets is increased by approximately % when tablets are taken with food (PDR, Martindale 33rd ed. Page 889). [000] Attempts have been made to improve the formulation of fenofibrate, especially as regards the bioavailability of fenofibrate. United States Patents Nos. 4,89,726 and,880,148 disclose co-micronizing the fenofibrate with surface active agents. United States Patent Nos. 6,074,670, 6,277, disclose micronized fenofibrate coated onto hydrosoluble carriers with optional surface active agents. United States Patent No. 6,814,977 discloses fenofibrate dissolved in a medium chain glycerol ester of fatty acid. United States Patent No. 6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol, or dimethylisosorbide and US Patent No.,827,36 discloses fenofibrate dissolved in diethyleneglycol monoethyl ether. [0006] Several patents disclose specific formulations of micronized fenofibrate with specific polymeric or surface active agent additives and other patents describe emulsions and suspensions of fenofibrate. For example, US Patent Application Publication No discloses fenofibrate of particle size less than 00 nm claimed to have an improved bioavailability. US Patent Application Publication No. 029 discloses microparticles of active pharmaceutical ingredients, drug delivery vehicles comprising same, and methods for making them. [0007] Micronization of the fenofibrate and combinations of micronized fenofibrate with surface active agents have moderately raised the bioavailability of fenofibrate allowing the agency-approved amount of drug dosed to be reduced from 0 mg per dose to 67 mg per dose and then subsequently to 4 mg per dose, whilst maintaining bioavailability in the fed state. Nanoparticle formulations of the drug have further allowed the reduction of the dose to 48 mg per dose with the bioavailability of the "fasted state" being reported as similar to the fed state. There is still room for much improvement because it is postulated that the true bioavailability of fenofibrate is still relatively low. SUMMARY OF THE INVENTION [0008] In one aspect, the present invention relates to a pharmaceutical composition comprising non-mechanically micronized microparticles of fenofibrate, especially sublimation micronized microparticles of fenofibrate using menthol as a sublimable carrier; polyethylene glycol, especially polyethylene glycol 6000; and a polyethylene-polypropylene glycol, especially poloxamer 7. The pharmaceutical composition can further include a pharmaceutical disintegrant selected from the group consisting of crospovidone, a carboxymethyl cellulose, especially crosslinked carboxymethylcellulose sodium (croscarmellose sodium), the bicarbonate or carbonate salts; especially alkali metal bicarbonates or carbonates like sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, magnesium carbonate, especially sodium bicarbonate; the organic carboxylic acids, especially citric acid, tanic acid, ascorbic acid, benzoic acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid, especially citric acid and tartaric acid; and combinations of any of the foregoing. [0009] In another aspect, the present invention relates to a solid oral dosage form including a pharmaceutical com- 2

3 position that includes about % to about % by weight of non-mechanically micronized microparticles of fenofibrate, especially sublimation micronized fenofibrate; about 7% to about 13% by weight poloxamer 7; about 7% to about 13% polyethylene glycol 6000; about % by weight microcrystalline cellulose; about 18% crospovidone by weight; about 12% sodium bicarbonate by weight; and about 12% by weight of either citric acid or tartaric acid. [00] In yet a further aspect, the present invention relates to a solid oral dosage form including a pharmaceutical composition that includes about % to about % by weight of non-mechanically micronized microparticles of fenofibrate, especially sublimation micronized fenofibrate; about 7% to about 13% by weight poloxamer 7; about 7% to about 13% polyethylene glycol 6000; about % by weight microcrystalline cellulose; about 18% crospovidone by weight; about 12% sodium bicarbonate by weight; and about 12% by weight of either citric acid or tartaric acid; wherein the dosage form has a time-dependent in vitro fenofibrate release profile such that at least about 1 % by weight, especially about 1 % to about 81% of the fenofibrate is released in about minutes, at least about 73%, especially about 73% to about 93%, by weight of the fenofibrate is released in about minutes, and at least about 8% by weight, especially about 8% by weight to essentially all of the fenofibrate is released in about minutes. [0011] In another aspect, the present invention relates to a solid oral dosage form, especially a compressed tablet, comprising a pharmaceutical composition that includes about 1 mg of sublimation micronized fenofibrate wherein in human in vivo pharmacokinetic studies in which the dosage form is administered in the fasted state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; the area under the AUC curve extrapolated to infinite time (AUC ) is about 1347 h*ng/g to about 3390 h*ng/g; and the maximum plasma concentration (C max ) is about 67 ng/g to about ng/g. Typically, such solid oral dosage form will exhibit an average AUC 48 of about 173 h*ng/g, an average AUC of about h*ng/g, and an average C max of about 70 ng/g. [0012] In still yet another aspect, the present invention relates to a solid oral dosage form, especially a compressed tablet, that includes a pharmaceutical composition having about 1 mg of sublimation micronized fenofibrate wherein, in human in vivo pharmacokinetic studies in which the dosage form is administered in the fed state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; the area under the AUC curve extrapolated to infinite time (AUC ) is about h*ng/g to about 8070 h*ng/g, and further wherein the average AUC 48 is about 011 h*ng/g and the average AUC is about h*ng/g. The dosage form can include a disintegrant. [0013] In yet a further aspect, the present invention relates to a pharmaceutical composition having a plurality of pharmaceutical carrier particles, especially particles of microcrystalline cellulose, having deposited thereon a combination of fenofibrate; especially about % to about % by weight fenofibrate; a polyethylene glycol, especially polyethylene glycol 6000 at about 7% to about 13% by weight; and a polyethylene-polypropylene glycol, especially poloxamer 7 at about 7% to about 13% by weight; wherein the combination is deposited by sublimation of a sublimable carrier, especially menthol, from a solid solution that comprises fenofibrate, the polyethylene glycol, the polyethylene-polypropylene glycol, and the sublimable carrier. The composition can also include a pharmaceutical disintegrant selected from the group consisting of crospovidone, a crosslinked carboxymethylcellulose salt (especially crosslinked carboxymethylcellulose sodium), the bicarbonate or carbonate salts; especially alkali metal bicarbonates or carbonates like sodium bicarbonate; the organic carboxylic acids, especially citric acid, tanic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; and combinations of any of the foregoing. [0014] In still yet a further aspect, the present invention relates to a solid oral dosage form that includes a pharmaceutical composition having about 1 mg of fenofibrate that has been deposited on a plurality of particles of microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution comprising fenofibrate and the sublimable carrier; wherein in human in vivo pharmacokinetic studies in which the dosage form is administered in the fasted state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; the area under the AUC curve extrapolated to infinite time (AUC ) is about 1347 h*ng/g to about 3390 h*ng/g; and the maximum plasma concentration (C max ) is about 67 ng/g to about ng/g. This solid oral dosage, in certain of its detailed aspects, exhibits an average AUC 48 of about 173 h*ng/g, an average AUC of about h*ng/g, and an average C max of about 70 ng/g. DETAILED DESCRIPTION OF THE INVENTION [00] In one embodiment, the present invention provides a pharmaceutical composition that includes non-mechanically micronized microparticles of fenofibrate, a polyethylene glycol, and a polyethylene-polypropylene glycol. [0016] Non-mechanically micronized microparticles have mean dimensions of about 0.1 m to about m and are produced by non-mechanical comminution techniques. Non-mechanical comminution techniques are techniques other than milling (ball, impingement, high energy), spray drying, and high-pressure homogenization. For purposes of the present application, the technique of lyophilization is considered a mechanical micronization technique and, hence, microparticles produced by lyophilization are excluded from non-mechanically micronized microparticles. Particle size measurement is well-known to the skilled artisan and can be accomplished by, for example, the well-known technique of laser light-scattering (Malvern Company). 3

4 [0017] The non-mechanically micronized microparticles of fenofibrate of the present invention can be obtained by, for example, the technique of sublimation micronization. Microparticles so obtained are referred to as "sublimation micronized" microparticles and the material of which such microparticle are comprised is referred to as "sublimation micronized". The technique of sublimation micronization is described in published United States Patent Application US 03/029 (Lerner et al.), herein incorporated in its entirety by reference. [0018] The microparticles of fenofibrate of the present invention are obtained via sublimation micronization by removing a sublimable carrier from a solid solution of fenofibrate in the sublimable carrier. The fenofibrate can be present with the sublimable carrier in the solid solution as discrete molecules, or it can be present in aggregates of a few hundred, a few thousand, or more molecules. The drug need only be dispersed on a sufficiently small scale so that sufficiently small, discrete microparticles are ultimately obtained. Preferably, the fenofibrate in the solid solution is dissolved in the sublimable carrier. [0019] Sublimable carriers have a measurable vapor pressure below their melting point. Preferred sublimable carriers have a vapor pressure of at least about Pascal, more preferably at least about Pascal at about C or more below their normal melting points. Preferably, the sublimable carrier has a melting point between about - C and about 0 C, more preferably between about C and about 60 C, most preferably between about C and about C. Preferably, the sublimable carrier is a substance that is classified by the United States Food and Drug Administration as generally recognized as safe (i.e., GRAS). Examples of suitable sublimable carriers include menthol, thymol, camphor, t-butanol, trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial), dimethylsulfone, urea, vanillin, camphene, salicylamide, and 2-aminopyridine. Menthol is a particularly preferred sublimable carrier. [00] The microparticles of the present invention are formed by removal of sublimable carrier from a solid solution, made as described above, at a temperature below the melting point of the solid solution. The solid solution must be kept at a temperature below its melting point to preserve the solid solution during the process of removing the sublimable carrier. The sublimable carrier can be removed from the solid solution by, for example, treating the solid solution, deposited on a pharmaceutical carrier particle where applicable as discussed infra, in a stream of air, preferably heated air, in, for example, a fluidized bed drier. [0021] The pharmaceutical compositions of the present invention further include polyalkylene glycols. Preferably the pharmaceutical compositions of the present invention include at least one polyethylene glycol (PEG) and at least one polyethylene-polypropylene glycol. [0022] Polyethylene glycols useful in the practice of the present invention have the general formula -(-CH 2 -CH 2 -O-) x - and can be characterized by the arithmetic mean value of X (<X N >) or the molecular weight corresponding thereto as described in, for example, Polyethylene Glycols, 23 National Formulary, 2 (United States Pharmacopeial Convention, 0). Polyethylene glycol 6000 is a preferred polyethylene glycol for use in the practice of the present invention. [0023] Polyethylene-polypropylene glycols useful in the practice of the present invention have the general structure -(O-CH 2 CH 2 -) a -O-(-CH(CH 3 )CH 2 -) b -(-O-CH 2 CH 2 -) a -OH and are commonly referred to as "poloxamers". Preferred poloxamers for use in the practice of the present invention are described in the monograph of like name in the U.S. National Formulary. Poloxamers, 23 National Formulary, 1 (United States Pharmacopeial Convention, 0). The polyethylene - polypropylene glycol commonly designated "poloxamer 7" is a particularly preferred polyethylenepolypropylene glycol for use in the practice of the present invention. [0024] The pharmaceutical compositions of the present invention can be and in preferred embodiments are deposited on a plurality of pharmaceutical carrier particles. Pharmaceutical carrier particles useful as support, substrate, or carrier for the pharmaceutical formulation of the present invention are made of comestible substances and are well known in the art. Examples of useful pharmaceutical carrier particles include particles, that can be non-pariel pellets, typically between about 0.1 mm. and about 2 mm. in diameter, and made of, for example, starch, particles of microcrystalline cellulose, lactose particles or, particularly, sugar particles. Suitable sugar particles (pellets, e.g. non-pariel 3, Nu-core, Nu-pariel) are commercially available in sizes from to mesh to 18 to 14 mesh. Preferred pharmaceutical carrier particles are made of non-hydrosoluble material, for example microcrystalline cellulose. Carrier particles comprised of microcrystalline cellulose (e.g. Avicel ) are particularly preferred pharmaceutical carrier particles. The skilled artisan knows other pellets or spheres useful as pharmaceutical carrier particles. [00] Pharmaceutical compositions according to the present invention can be made by combining fenofibrate, polyethylene glycol, polyethylene- polypropylene glycol, and a sublimable carrier. The above components can be combined neat or, in embodiments in which the composition is deposited on a plurality of pharmaceutical carrier particles, together with a suitable solvent. Suitable solvents dissolve fenofibrate, polyethylene glycol, polyethylene - polypropylene glycol, and the sublimable carrier, but do not dissolve pharmaceutical carrier particles and further are chemically inert to any of the components, and can be readily removed at a convenient temperature, especially a temperature < 0 C, optionally with the aid of an applied vacuum. Ethanol is an example of a suitable solvent. [0026] The combination of components are combined and warmed to form a homogeneous mixture, preferably a solution, and cooled to obtain a solid solution. The fenofibrate can be present with the sublimable carrier in the solid solution as discrete molecules, or it can be present in aggregates of a few hundred, a few thousand, or more molecules. 4

5 The drug need only be dispersed on a sufficiently small scale so that sufficiently small, discrete microparticles are ultimately obtained. [0027] Preferably, the drug in the solid solution is dissolved in the sublimable carrier. In embodiments in which the sublimation micronized microparticles are deposited on a plurality of pharmaceutical carrier particles, the warm solution of components in sublimable carrier is combined with pharmaceutical carrier particles, for example by mixing, and the combination allowed to cool to form the solid solution on the pharmaceutical carrier particles. Alternatively, pharmaceutical carrier particles are combined with a solution of sublimable carrier, fenofibrate, polyethylene glycol, and polyethylene - polypropylene glycol in a suitable solvent (e.g. ethanol). The solvent is removed, optionally with the aid of applied heat and vacuum, to obtain pharmaceutical carrier particles having deposited thereon a solid solution of the fenofibrate, polyethylene glycol, and polyethylene - polypropylene glycol in the sublimable carrier (e.g. menthol). [0028] After formation of the solid solution, whether deposited on pharmaceutical carrier particles or not, the pharmaceutical formulations of the present invention are subsequently formed by removal of sublimable carrier from the solid solution, made as described above, at a temperature below the melting point of the solid solution. The solid solution must be kept at a temperature below its melting point to preserve the solid solution during the process of removing the sublimable carrier. The sublimable carrier can be removed from the solid solution by, for example, treating the solid solution, deposited on a pharmaceutical carrier particle where applicable, in a stream of air, preferably heated air, in, for example, a fluidized bed drier. [0029] In preferred embodiments, removal of the sublimable carrier results in formation of non-mechanically micronized microparticles of fenofibrate, which microparticles can further contain at least a portion of the polyethylene glycol and polyethylene-polypropylene glycol. Furthermore, at least a portion of the fenofibrate can be in solution or intimately associated with either or both of the polyethylene glycol and polyethylene-polypropylene glycol that are not necessarily with the non-mechanically micronized microparticles. [00] Applicants invention is not limited by a particular theory of operation. But applicants believe that, after removal of the sublimable carrier, at least a portion of the fenofibrate is dissolved in or intimately associated with the polyalkylene glycols. The expression "intimately associated" excludes a simple physical mixture such as can be achieved by, for example, dry blending, dry granulation, or wet granulation in the presence of a liquid that does not at least partially dissolve the components. [0031] The pharmaceutical compositions of the present invention, particularly when deposited on a plurality of pharmaceutical carrier particles, are well suited for manufacture of liquid and especially solid oral dosage forms such as compressed tablets and filled capsules. In another embodiment, the present invention provides oral dosage forms, especially solid oral dosage forms, preferably compressed tablets, that include the pharmaceutical compositions of the present invention. [0032] Compressed tablets are formulated from pharmaceutical compositions containing the microparticles of the pharmacologically active substance or drug, or using pharmaceutical carrier particles bearing such microparticles, and pharmacologically inert (pharmaceutically acceptable) additives or excipients. [0033] For making a tablet, it will typically be desirable to include one or more benign pharmaceutical excipients in the pharmaceutical composition. The pharmaceutical composition of the present invention may contain one or more diluents added to make the tablet larger and, hence, easier for the patient and caregiver to handle. Common diluents are microcrystalline cellulose (e.g. Avicel ), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc. [0034] Binders also may be included in tablet formulations to help hold the tablet together after compression. Some typical binders are acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e,g. Klucel ), hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon, Plasdone ), pregelatinized starch, sodium alginate and starch. [00] The tablet may further include a disintegrant to accelerate disintegration of the tablet in the patient s stomach. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, crosslinked carboxymethylcellulose sodium or calcium (croscarmellose sodium (e.g. Ac-Di-Sol, Primellose or croscarmelose calcium), crospovidone (e.g. Kollidon, Polyplasdone ), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ) and starch. [0036] In addition to or in place of alginic acid, other organic carboxylic acids can be included in the formulation. The organic acids include tannic acid, citric acid, fumaric acid tartaric acid, lactic acid, malic acid, ascorbic acid, benzoic acid, sorbic acid, and the like. Tannic acid and citric acid are particularly preferred organic carboxylic acids for use in this and other embodiments of the present invention. [0037] The pharmaceutical compositions of the present invention can, and in preferred embodiments do contain a

6 bicarbonate or carbonate, especially an alkali metal bicarbonate or carbonate. Examples of preferred alkali metal carbonates and bicarbonates include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate. Alkailne earth metal carbonates like calcium carbonate and magnesium carbonate can also be used. [0038] A pharmaceutical composition for making compressed tablets may further include glidants, lubricants, flavorings, colorants and other commonly used excipients. [0039] Pharmaceutical carrier particles bearing microparticles of a drug made in accordance with the present invention have excellent bulk flow properties and can be used directly, alone or in combination with carrier particles that do not carry a drug, to make capsule dosage forms. If necessary, diluents such as lactose, mannitol, calcium carbonate, and magnesium carbonate, to mention just a few, can be formulated with the microparticle-bearing pharmaceutical carrier particles when making capsules [00] Liquid oral pharmaceutical compositions of the present invention comprise microparticles or microparticlebearing pharmaceutical carrier particles and a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin, most preferably water. [0041] Liquid oral pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition the active ingredient, drug delivery vehicle, or excipient having low solubility in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol. [0042] Liquid oral pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum. [0043] The liquid oral pharmaceutical composition also may contain sweetening agents, such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar; preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid; and buffers such as guconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. [0044] Solid oral dosage forms formulated and compounded with the sublimation micronized microparticles of fenofibrate together with a polyethylene glycol and a polyethylene-polypropylene glycol, prepared as hereinabove described, provide for improved bioavailability of fenofibrate as demonstrated by both in vitro dissolution (release) and human in vivo pharmacokinetic (plasma concentration) testing. The results of both in vivo and in vitro testing disclosed herein were obtained with tablets containing about 1 mg fenofibrate and having a nominal weight of 792 mg each. [00] Time-dependent in vitro release (dissolution) profiles disclosed herein were obtained at 37 C using a USP Type-II dissolution tester operating at rpm and filled with 00 ml of 0. wt-% sodium lauryl sulfate in water. The concentration of fenofibrate in the test liquid was determined by HPLC. [0046] Pharmacokinetic data disclosed herein were obtained in human in vivo experiments by determining the blood plasma concentration of the metabolite, fenofibric acid, as a function of time to afford a well-know Boltzmann-shaped cumulative plasma concentration (AUC) curve. Individual points are reported with reference to selected actual or extrapolated time points on the AUC curve. [0047] Thus, the area under the 48-hour AUC curve, AUC 48, refers to the cumulative blood concentration up to the 48 hour time point (the last point measured). AUC refers to the area under the AUC curve extrapolated to infinite time. C max refers to the maximum absolute plasma concentration measured in the 48 hour test (i.e. the maximum point on the 48-hour AUC curve). Average AUC (<AUC>) is the arithmetic average plasma concentration of fenofibric acid measured over the course of the plasma concentration measurement period (about 48 hours). [0048] The present invention, in certain of its embodiments, is illustrated by the following non-limiting examples. In the following examples, fed state means that the subject has not taken food within the ten hours preceding dosing. Fed state means that the subject has taken food about one-half hour prior to dosing. EXPERIMENTAL [0049] A. Fenofibrate granulate [00] Menthol (1.333Kg) was melted in a glass reactor at C, with stirring. Fenofibrate (133.3 gm), poloxamer 7 (Lutrol F127, 76 gm), and polyethylene glycol 6000 (76 gm) were charged to the reactor. The menthol melt was stirred at C until all the components had dissolved. Microcrystalline cellulose (Avicel PH 1, 6.7 gm) was added to the melt, which was stirred until a uniform suspension was obtained. [001] The menthol melt was divided into three equal portions and poured into three trays (stainless steel, m 2 each) that were cooled to - C for quick solidification of the menthol suspension. The solid material on the trays was 6

7 removed and coarsely milled through a 2. mm screen using an Erweka mill. The obtained powder was again divided into three portions and returned to the trays. Menthol was removed from the material on the trays by sublimation in a high vacuum tray drier at 0.2 mbar and 36 C for about 3 hours. The resulting powder was removed from the trays and milled through a 1.6 mm screen using an Erweka mill so as to not effect substantial comminution of the already-formed particles. The granulate so obtained was weighed (346.4 gm) for a yield of 88%. [002] B. Fenofibrate Tablets (1 mg)- [003] The Fenofibrate granulate from step A was milled through a 0.8 mm screen using an Erweka mill. The milled granulate (336 gm) was added to a polyethylene bag ( x 70 cm). Crospovidone (8 gm), sodium bicarbonate (72 gm) and citric acid anhydrous (72 gm) were added and the blend mixed for minutes. Magnesium stearate (12 gm) was added to the bag and the blend mixed for a further 1/2 minute. The total amount of blend so obtained was 600 grams. [004] The blend was compressed into tablets on a Manesty F3 single punch tabletting machine using oval shaped (8.8 mm x 17.6 mm) normal concave punches. Tablet design weight was 78 mg 39.3 mg at a hardness of - 7 Kp. The tablets obtained had an average weight of 792 mg and a hardness of 6 Kp. Several batches were made and labeled MAZ 149B, MAZ149B1 and MAZ149B2, respectively. [00] C In vitro release [006] The release (dissolution) of fenofibrate from the tablets was tested using a USP type II dissolution tester filled with 00 ml 0.% sodium lauryl sulfate (SLS) (w/v) in water at 37 C and revolutions per minute (rpm). The amount of fenofibrate in each sample was determined by HPLC as above. The results are given in tables C1-C3 for three batches. Table C1. Results of in vitro release of fenofibrate (% label claim) MAZ149B Time(min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel Vessel 6 Vessel Time(min) Vessel 8 Vessel 9 Vessel Vessel 11 Vessel 12 Avg %RSD Table C2. Results of in vitro release of fenofibrate (% label claim) MAZ149B1 Time(min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel Vessel 6 Avg %RSD Table C3. Results of in vitro release of fenofibrate (% label claim) MAZ149B2 Time(min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel Vessel 6 Avg %RSD [007] D. In vivo pharmacokinetic trial [008] Pharmacokinetic Test of MAZ149B and TriCor 1 mg (NDA # 19-4/S-00). [009] A four way crossover bioequivalence pharmacokinetic trial was carried out in 12 healthy volunteers using MAZ149B (1 mg, described supra) and TriCor (1 mg) as two of the test arms. The other two arms were other test formulations prepared according to the present invention. A one week washout was taken between each arm of the test. 7

8 Blood samples were taken at 0, 1, 2, 3, 3., 4, 4.,,., 6, 6., 7, 8, 9,, 12, 16, 24 and 48 hours (19 samples per trial) and analyzed for fenofibric acid by a validated method. The 4 arm trials were carried out in both the fasted and fed states. [0060] Results [0061] Fasted-state data was obtained for volunteers 1-11 for the test MAZ 149B (N=11) and for volunteers 2-11 for the reference TriCor (N-). The results are collected in table D1. The average values showed the bioavailability of the test to be 97.4% of the reference based on AUC 48 (17334 vs h*ng/g) and 97.7% of the reference based on AUC (21363 vs h*ng/g). The corresponding geometric mean values showed 97.% based on AUC 48 ( vs h*ng/g) and 97.% based on AUC (217 vs. 28 h*ng/g). The geometric mean of the ratio of the individual ratios of test to reference AUC was The average values for C max showed the test to be 99% of the reference (70 vs. 624 ng/g) and the geometric mean to be 0.7% (3 vs. 270 ng/g). The geometric mean of the ratios of the test to reference of the individual volunteers was The variability of the bioavailability was very similar 28.9% vs % for %CV (variation in the variable) of the AUC 48 values. The average terminal half life (terminal half-life for elimination) was.0 hours for the test product and 19.9 hours for the reference while the average T max was 2. hours for the test and 2.1 hours for the reference. One can conclude that the two formulations are bioequivalent in the fasted state. [0062] Fed-state data was obtained for volunteers 1-, 7- and 12 (N=) for both the test MAZ149B and the TriCor reference product. The results are collected in table D2. The average values showed the bioavailability of the test to be7.1 % of the reference based on AUC 48 (011 vs h*ng/g) and 112.0% of the reference based on AUC (18149 vs. 163 h*ng/g). The corresponding geometric mean values showed 6.8% based on AUC 48 (12 vs h*ng/g) and 111.2% based on AUC (1721 vs. 69 h*ng/g). The geometric mean of the ratio of the individual ratios of test to reference AUC was The average values for C max showed the test to be 79.0 % of the reference (77 vs.967 ng/g) and the geometric mean to be 77.% (7147 vs ng/g). The geometric mean of the ratios of the test to reference of the individual volunteers was The variability of the bioavailability was very similar 27.16% vs % for %CV (variation in the value) of the AUC 48 values. The average terminal half life was 17.4 hours for the test product and 16.1 hours for the reference while the average Tmax was 8.0 hours for the test and 3.6 hours for the reference. The improved bioavailability coupled to a lower C max and the later Tmax indicate an improved product in the fed state. [0063] Further aspects and features of the present inventions are set out in the following numbered clauses. 1. A pharmaceutical composition comprising non-mechanically micronized microparticles of fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol. 2. The pharmaceutical composition of clause 1 wherein the non-mechanically micronized microparticles of fenofibrate are made by sublimation micronization. 3. The pharmaceutical composition of any preceding clause wherein the non-mechanically micronized microparticles are deposited on a plurality of pharmaceutical carrier particles. 4. The pharmaceutical composition of clause 3 wherein menthol is the sublimable carrier in the sublimation micronization step.. The pharmaceutical composition of any preceding clause wherein the polyethylene glycol is polyethylene glycol The pharmaceutical composition of any preceding clause wherein the polyethylene-polypropylene glycol is poloxamer The pharmaceutical composition of clause 6 wherein the pharmaceutical composition is in the form of a solid oral dosage form comprising about % to about % by weight fenofibrate, about 7% to about 13% poloxamer 7, and about 7% to about 13% polyethylene glycol The pharmaceutical composition any preceding clause further comprising a pharmaceutical disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, the bicarbonate or carbonate salts, the organic carboxylic acids, and combinations of any of the foregoing. 9. The pharmaceutical composition of clause 8 wherein the organic carboxylic acids are selected from citric acid, tanic acid, ascorbic acid, benzoic acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid, especially 8

9 citric acid and tartaric acid.. The pharmaceutical composition of clause 9 comprising about 12% by weight of either citric acid or tartaric acid, especially about 12% by weight of citric acid. 11. The pharmaceutical composition of clause 8 wherein the bicarbonate or carbonate salts are alkali metal bicarbonates or carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, magnesium carbonate, especially sodium bicarbonate. 12. The pharmaceutical composition of clause 11 comprising about 12% by weight of sodium bicarbonate. 13. The pharmaceutical composition of any preceding clause further comprising microcrystalline cellulose, particularly about % by weight of microcrystalline cellulose. 14. The pharmaceutical composition of any preceding clause further comprising crosspovidone, particularly about 18% by weight of crosspovidone.. The pharmaceutical composition of any preceding clause in solid oral dosage form, especially a compressed tablet. 16. The solid oral dosage form of clause having a time-dependent in vitro fenofibrate release profile such that at least about 1 % by weight of the fenofibrate is released in about minutes, at least about 73% by weight of the fenofibrate is released in about minutes, and at least about 8% by weight of the fenofibrate is released in about minutes. 17. The solid oral dosage form of clause having a time-dependent in vitro release profile such that about 1 % to about 81 % by weight of the fenofibrate is released in about minutes, about 73% to about 93% by weight of the fenofibrate is released in about minutes, and about 8% by weight to about all of the fenofibrate is released in about minutes. 18. A solid oral dosage form comprising a pharmaceutical composition comprising about 1 mg of sublimation micronized fenofibrate wherein in human in vivo pharmacokinetic studies in which the dosage form is administered in the fasted state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; the area under the AUC curve extrapolated to infinite time (AUC ) is about 1347 h*ng/g to about 3390 h*ng/g; and the maximum plasma concentration (C max ) is about 67 ng/g to about ng/g. 19. The solid oral dosage form of clause 18 wherein, in human in vivo pharmacokinetic studies in which the dosage form is administered in the fasted state, the average AUC 48 is about 173 h*ng/g, the average AUC is about h*ng/g, and the average C max is about 70 ng/g.. A solid oral dosage form comprising a pharmaceutical composition comprising about 1 mg of sublimation micronized fenofibrate wherein in human in vivo pharmacokinetic studies in which the dosage form is administered in the fed state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; and the area under the AUC curve extrapolated to infinite time (AUC ) is about h*ng/g to about 8070 h*ng/g. 21. The solid oral dosage form of clause 17 wherein the average AUC 48 is about 011 h*ng/g and the average AUC is about h*ng/g. 22. The solid oral dosage form of any of clauses 16 to 21 wherein the solid oral dosage form is a compressed tablet. 23. A pharmaceutical composition comprising a plurality of pharmaceutical carrier particles having deposited thereon a combination of fenofibrate, a polyethylene glycol, and a polyethylene-polypropylene glycol, wherein the combination is deposited by sublimation of a sublimable carrier from a solid solution that comprises fenofibrate, the polyethylene glycol, the polyethylene-polypropylene glycol, and the sublimable carrier. 24. The pharmaceutical composition of clause 23 wherein the sublimable carrier is menthol.. The pharmaceutical composition of any of clauses 23 to 24 wherein the polyethylene glycol is polyethylene 9

10 glycol The pharmaceutical composition of any of clauses 23 to wherein the polyethylene-polypropylene glycol is poloxamer The pharmaceutical composition of any of clauses 23 to 26 wherein the pharmaceutical composition is in the form of a solid oral dosage form comprising about % to about % by weight fenofibrate, about 7% to about 13% poloxamer 7, and about 7% to about 13% polyethylene glycol The pharmaceutical composition of any of clauses 23 to 26 further comprising a pharmaceutical disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, the bicarbonate or carbonate salts, the organic carboxylic acids, and combinations of any of the foregoing. 29. The pharmaceutical composition of clause 28 wherein the organic carboxylic acids are selected from citric acid, tanic acid, ascorbic acid, benzoic acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid, especially citric acid and tartaric acid.. The pharmaceutical composition of clause 29 comprising about 12% by weight of either citric acid or tartaric acid, especially about 12% by weight of citric acid. 31. The pharmaceutical composition of clause 28 wherein the bicarbonate or carbonate salts are alkali metal bicarbonates or carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, magnesium carbonate, especially sodium bicarbonate. 32. The pharmaceutical composition of clause 31 comprising about 12% by weight of sodium bicarbonate. 33. The pharmaceutical composition of any of clauses 23 to 32 further comprising microcrystalline cellulose, particularly about % by weight of microcrystalline cellulose. 34. The pharmaceutical composition of any of clauses 23 to 33 further comprising crosspovidone, particularly about 18% by weight of crosspovidone.. The pharmaceutical composition of any of clauses 23 to 34 in solid oral dosage form, especially a compressed tablet. 36. A solid oral dosage form comprising a pharmaceutical composition comprising about % to about % by weight of fenofibrate, about 7% to about 13% by weight poloxamer 7, about 7% to about 13% polyethylene glycol 6000, about % by weight microcrystalline cellulose, about 18% by weight crosspovidone, about 12% by weight sodium bicarbonate, and about 12% by weight of either citric acid or tartaric acid, wherein at least the fenofibrate, the poloxamer 7, and the polyethylene glycol 6000 are deposited on the microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution of at least the fenofibrate, the poloxamer 7, and the polyethylene glycol 6000 with the sublimable carrier. 37. The solid oral dosage form of clause 36 comprising about 12% by weight citric acid. 38. The solid oral dosage form of clause 36 or 37 having a time-dependent in vitro fenofibrate release profile such that at least about 1% by weight of the fenofibrate is released in about minutes, at least about 73% by weight of the fenofibrate is released in about minutes, and at least about 8% by weight of the fenofibrate is released in about minutes. 39. The solid oral dosage form of clause 36 or 37 having a time-dependent in vitro release profile such that about 1% to about 81% by weight of the fenofibrate is released in about minutes, about 73% to about 93% by weight of the fenofibrate is released in about minutes, and about 8% by weight to about all of the fenofibrate is released in about minutes.. A solid oral dosage form comprising a pharmaceutical composition comprising about 1 mg of fenofibrate that has been deposited on a plurality of particles of microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution comprising fenofibrate and the sublimable carrier; wherein in human in vivo pharmacokinetic

11 studies in which the dosage form is administered in the fasted state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; the area under the AUC curve extrapolated to infinite time (AUC ) is about 1347 h*ng/g to about 3390 h*ng/g; and the maximum plasma concentration (C max ) is about 67 ng/g to about ng/g. 41. The solid oral dosage form of clause wherein, in human in vivo pharmacokinetic studies in which the dosage form is administered in the fasted state, the average AUC 48 is about 173 h*ng/g, the average AUC is about h*ng/g, and the average C max is about 70 ng/g. 42. A solid oral dosage form comprising a pharmaceutical composition comprising about 1 mg of fenofibrate that has been deposited on a plurality of particles of microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution comprising fenofibrate and the sublimable carrier; wherein in human in vivo pharmacokinetic studies in which the dosage form is administered in the fed state, the area under the 48-hour AUC curve (AUC 48 ) is about h*ng/g to about h*ng/g; and the area under the AUC curve extrapolated to infinite time (AUC ) is about h*ng/g to about 8070 h*ng/g. 43. The solid oral dosage form of clause 42 wherein the average AUC48 is about 011 h*ng/g and the average AUC is about h*ng/g. 44. The solid oral dosage form of any of clauses 36 to 44 wherein the solid oral dosage form is a compressed tablet. 11

12 12 RESULTS OF Table D1 (Fasted State) fenofibric acid fasted state MAZ149B vs. TriCor dose test (mg)= 1 dose ref (mg) = 1 volunteer AUC 48 (h*ng/g) AUCinf (h*ng/g) t1/2 Tmax (h) Cmax (ng/g) 1 (test) Cmaxtest/ Cmaxref 2 (test) (test) (test) (Test) (test) (test) (test) (test) (test) (test) (test) AUCinftest/ AUCinfref EP A1 1 (ref) 2 (ref) (ref) (ref) (ref) (ref) (ref) (ref)

13 RESULTS OF (continued) fenofibric acid fasted state MAZ149B vs. TriCor dose test (mg)= 1 dose ref (mg) = 1 volunteer AUC 48 (h*ng/g) AUCinf (h*ng/g) t1/2 Tmax (h) Cmax (ng/g) 9 (ref) (ref) (ref) (ref) Cmaxtest/ Cmaxref AUCinftest/ AUCinfref AVG(test) AVG (ref) Geomn(test) Geomn(ref) stddev(test) stddev(ref) EP A1 %CV (test) 28.9% 31.04% %CV (ref) 27.16% 27.93%

14 14 Table D2 (Fed State) RESULTS OF fenofibric acid fed state 3600-MAZ149B vs. TriCor dose test (mg)= 1 dose ref (mg) = 1 volunteer AUC 48 (h*ng/g) AUC 48 inf (h*ng/g) t1/2 Tmax (h) Cmax (ng/g) Cmaxtest/ Cmaxref 1 (test) (test) (test) (test) (Test) (test) 7 (test) (test) (test) (test) (test) 12 (test) AUCinftest/ AUCinfref EP A1 1 (ref) (ref) (ref) (ref) (ref) (ref) 7 (ref) (ref) (ref)